Antimycobacterial Activity of Alkaloids and Extracts from Tabernaemontana alba and T. arborea

Abstract

Tuberculosis is the main cause of death from a single infectious agent. Globally, according to the World Health Organization, in 2018, there were an estimated 1.2 million tuberculosis deaths. Moreover, there is a continuous appearance of drug-resistant strains. Thus, development of new antituberculosis medicines should receive high priority. Plant-derived natural products are promising candidates for this purpose. We therefore screened alkaloid extracts obtained from the root and stem barks of the Mexican Apocynaceae species Tabernaemontana alba and Tabernaemontana arborea, as well as the pure alkaloids ibogaine, voacangine, and voacamine, tested for activity against Mycobacterium tuberculosis H37Rv and cytotoxicity to mammalian Vero cells using the resazurin microtiter and the MTT assays, respectively. The extracts were analyzed by GC-MS and HPLC-UV. T. arborea root bark alkaloid extract showed the highest activity against M. tuberculosis (MIC100 = 7.8 µg/mL) of the four extracts tested. HPLC suggested that voacangine and voacamine were the major components. The latter was isolated by column chromatography, and its chemical structure was elucidated by 1H and 13C NMR, and MS. Unambiguous assignation was performed by HSQC, HMBC, and NOESY experiments. Voacamine is a dimeric bis-indole-type alkaloid and is 15 times more potent than the monomeric ibogan-type alkaloids ibogaine and voacangine (MIC100 = 15.6, 250.0, and 250.0 µg/mL, respectively). However, all of these compounds showed cytotoxicity to Vero cells, with a poor selectivity index of 1.00, 0.16, and 1.42, respectively. This is the first report of voacamine activity against M. tuberculosis.

Plant-Based Indole Alkaloids: A Comprehensive Overview from a Pharmacological Perspective

“…The compound showed inhibitory activity against the causative agent of tuberculosis, Mycobacterium tuberculosis . The results showed that the MIC and the IC 50 values were 15.60 and 16.30 µg/mL, respectively ( Table 1 , Figure 19 ) [ 58 ].…”

Potent Anti-amoebic Effects of Ibogaine, Voacangine and the Root Bark Alkaloid Fraction of Tabernaemontana arborea

“…In a previous report, our group identified MIAs ibogaine and voacangine in T. arborea root bark methanol extract [21]. In contrast to the moderate antimycobacterial activity shown by these alkaloids (IC 50 between 16 and 40 µg/mL), both showed potent amoebicidal activity, causing the death of all parasites in 24 h at a concentration of 10 µg/mL and yielding an IC 50 between 1.4 and 3.5 µg/mL, as mentioned above.…”

“…Studies in India [33] demonstrated that Tabernaemontana spp. roots have also been reported to be anti-amoebic, although * Cytotoxic Concentration 50 previously reported in [21], except for metronidazole, which was previously reported by us in [30]; SI: Selectivity Index (CC 50 / IC 50 ); ND: Not determine no information was provided on effective concentrations for the extracts. In a unique experimental antique report on the effect of ethanolic extracts from 15 Tabernaemontana species from Africa, Asia, and Guyana, on E. histolytica DU strain, it was found that extracts from leaves and root and stem barks of all species showed significant activity killing most amoebae at 4.5 mg/mL, whereas extracts from only three species, stem barks of T. contorta, stem barks of T. penduliflora, and leaves of T. psorocarpa, showed some activity at 0.45 mg/mL [34].…”

“…Crude extracts from the root bark were obtained by extraction with methanol, from which the alkaloid fraction was obtained by acid-base extraction and analyzed by GC-MS, and HPLC as described in [21], and where the chromatograms can be consulted. Pure ibogaine and voacangine kindly donated by Phytostan Enterprises, Inc. were used as external standards in these analyses.…”

“…For instance, T. alba Mill., a species found from the south of México to Panama, is used in traditional medicine to treat skin conditions due to their anti-inflammatory, analgesic, and anti-microbial properties [15]. In addition to the well-known antibacterial effect of extracts and alkaloid fractions of several Tabernaemontana species plants [16][17][18][19][20][21], anti-parasitic effects have also been reported, including extracts and alkaloids from T. citrifolia on the gastrointestinal nematode Haemonchus contortus [22], T. elegans, T. pachysiphon, T. peduncularis and T. macrocarpa on the malarial protozoan Plasmodium falciparum [23][24][25][26], T. pandacaqui on the protozoan Trypanosoma cruzi, causal agent of Chagas disease [27] and T. longipes on Trypanosoma brucei, the causal agent of African sleeping sickness [28]. Previous phytochemical research has shown T. arborea root bark to be particularly rich in monoterpenoid indole alkaloids (MIAs), including ibogaine, voacangine, and vobasine, as well as the bis-indole type alkaloid voacamine [21,29].…”